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1.  Ziprasidone as an adjuvant for clozapine- or olanzapine-associated medical morbidity in chronic schizophrenia 
Human psychopharmacology  2009;24(3):225-232.
This study sought to examine the effect of ziprasidone on olanzapine or clozapine associated medical morbidity such as insulin resistance, diabetes mellitus and impaired fasting glucose, obesity and hyperlipidemia in patients with schizophrenia or schizoaffective disorder.
This was a six-week, open label trial of ziprasidone 160 mg/day added to a stable dose of olanzapine or clozapine in twenty-one schizophrenia or schizoaffective patients with diabetes mellitus, impaired fasting glucose, or insulin resistance.
Ten olanzapine-treated subjects and eleven clozapine-treated subjects were enrolled in the study. There were no significant differences between the two groups at baseline for age, gender, education, ethnicity, BMI, cholesterol levels, or fasting glucose. At week six, there were no significant changes in weight, BMI, cholesterol levels, or fasting glucose. There was no significant difference in psychotic, negative or depressive symptoms. QTc significantly increased at week 2 but not at week 6.
The addition of 160 mg/day of ziprasidone was well tolerate but did not produce significant improvement in fasting glucose, insulin resistance, hyperlipidemia or lead to weight loss in olanzapine- or clozapine-treated subjects with schizophrenia or schizoaffective disorder.
PMCID: PMC4327763  PMID: 19283774
clozapine; olanzapine; ziprasidone; weight; lipids; insulin resistance; schizophrenia
2.  Age-at-Onset in Late Onset Alzheimer Disease is Modified by Multiple Genetic Loci 
JAMA neurology  2014;71(11):1394-1404.
As APOE locus variants contribute to both risk of late-onset Alzheimer disease and differences in age-at-onset, it is important to know if other established late-onset Alzheimer disease risk loci also affect age-at-onset in cases.
To investigate the effects of known Alzheimer disease risk loci in modifying age-at-onset, and to estimate their cumulative effect on age-at-onset variation, using data from genome-wide association studies in the Alzheimer’s Disease Genetics Consortium (ADGC).
Design, Setting and Participants
The ADGC comprises 14 case-control, prospective, and family-based datasets with data on 9,162 Caucasian participants with Alzheimer’s occurring after age 60 who also had complete age-at-onset information, gathered between 1989 and 2011 at multiple sites by participating studies. Data on genotyped or imputed single nucleotide polymorphisms (SNPs) most significantly associated with risk at ten confirmed LOAD loci were examined in linear modeling of AAO, and individual dataset results were combined using a random effects, inverse variance-weighted meta-analysis approach to determine if they contribute to variation in age-at-onset. Aggregate effects of all risk loci on AAO were examined in a burden analysis using genotype scores weighted by risk effect sizes.
Main Outcomes and Measures
Age at disease onset abstracted from medical records among participants with late-onset Alzheimer disease diagnosed per standard criteria.
Analysis confirmed association of APOE with age-at-onset (rs6857, P=3.30×10−96), with associations in CR1 (rs6701713, P=7.17×10−4), BIN1 (rs7561528, P=4.78×10−4), and PICALM (rs561655, P=2.23×10−3) reaching statistical significance (P<0.005). Risk alleles individually reduced age-at-onset by 3-6 months. Burden analyses demonstrated that APOE contributes to 3.9% of variation in age-at-onset (R2=0.220) over baseline (R2=0.189) whereas the other nine loci together contribute to 1.1% of variation (R2=0.198).
Conclusions and Relevance
We confirmed association of APOE variants with age-at-onset among late-onset Alzheimer disease cases and observed novel associations with age-at-onset in CR1, BIN1, and PICALM. In contrast to earlier hypothetical modeling, we show that the combined effects of Alzheimer disease risk variants on age-at-onset are on the scale of, but do not exceed, the APOE effect. While the aggregate effects of risk loci on age-at-onset may be significant, additional genetic contributions to age-at-onset are individually likely to be small.
PMCID: PMC4314944  PMID: 25199842
Alzheimer Disease; Alzheimer Disease Genetics; Alzheimer’s Disease - Pathophysiology; Genetics of Alzheimer Disease; Aging
3.  Oncogenic KRAS promotes malignant brain tumors in zebrafish 
Molecular Cancer  2015;14(1):18.
Zebrafish have been used as a vertebrate model to study human cancers such as melanoma, rhabdomyosarcoma, liver cancer, and leukemia as well as for high-throughput screening of small molecules of therapeutic value. However, they are just emerging as a model for human brain tumors, which are among the most devastating and difficult to treat. In this study, we evaluated zebrafish as a brain tumor model by overexpressing a human version of oncogenic KRAS (KRASG12V).
Using zebrafish cytokeratin 5 (krt5) and glial fibrillary acidic protein (gfap) gene promoters, we activated Ras signaling in the zebrafish central nervous system (CNS) through transient and stable transgenic overexpression. Immunohistochemical analyses were performed to identify activated pathways in the resulting brain tumors. The effects of the MEK inhibitor U0126 on oncogenic KRAS were evaluated.
We demonstrated that transient transgenic expression of KRASG12V in putative neural stem and/or progenitor cells induced brain tumorigenesis. When expressed under the control of the krt5 gene promoter, KRASG12V induced brain tumors in ventricular zones (VZ) at low frequency. The majority of other tumors were composed mostly of spindle and epithelioid cells, reminiscent of malignant peripheral nerve sheath tumors (MPNSTs). In contrast, when expressed under the control of the gfap gene promoter, KRASG12V induced brain tumors in both VZs and brain parenchyma at higher frequency. Immunohistochemical analyses indicated prominent activation of the canonical RAS-RAF-ERK pathway, variable activation of the mTOR pathway, but no activation of the PI3K-AKT pathway. In a krt5-derived stable and inducible transgenic line, expression of oncogenic KRAS resulted in skin hyperplasia, and the MEK inhibitor U0126 effectively suppressed this pro-proliferative effects. In a gfap-derived stable and inducible line, expression of oncogenic KRAS led to significantly increased mitotic index in the spinal cord.
Our studies demonstrate that zebrafish could be explored to study cellular origins and molecular mechanisms of brain tumorigenesis and could also be used as a platform for studying human oncogene function and for discovering oncogenic RAS inhibitors.
Electronic supplementary material
The online version of this article (doi:10.1186/s12943-015-0288-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4320811  PMID: 25644510
Zebrafish; Oncogenic KRAS (KRASG12V); krt5; gfap; Brain tumors; Drug screening
4.  A web-based intervention for abused women: the New Zealand isafe randomised controlled trial protocol 
BMC Public Health  2015;15:56.
Intimate partner violence (IPV) and its associated negative mental health consequences are significant for women in New Zealand and internationally. One of the most widely recommended interventions is safety planning. However, few women experiencing violence access specialist services for safety planning. A safety decision aid, weighing the dangers of leaving or staying in an abusive relationship, gives women the opportunity to prioritise, plan and take action to increase safety for themselves and their children. This randomised controlled trial is testing the effectiveness of an innovative, interactive web-based safety decision aid. The trial is an international collaborative concurrent replication of a USA trial (IRIS study NCT01312103), regionalised for the Aotearoa New Zealand culture and offers fully automated online trial recruitment, eligibility screening and consent.
In a fully automated web-based trial (isafe) 340 abused women will be randomly assigned in equal numbers to a safety decision aid intervention or usual safety planning control website. Intervention components include: (a) safety priority setting, (b) danger assessment and (c) an individually tailored safety action plan. Self-reported outcome measures are collected at baseline and 3, 6, and 12-months post-baseline.
Primary outcomes are depression (measured by Center for Epidemiologic Studies Depression Scale, Revised) and IPV exposure (measured by Severity Violence Against Women Scale) at 12 months post-baseline. Secondary outcomes include PTSD, psychological abuse, decisional conflict, safety behaviors and danger in the relationship.
This trial will provide much-needed information on the potential relationships among safety planning, improved mental health, reduced violence as well as decreased decisional conflict related to safety in the abusive relationship. The novel web-based safety decision aid intervention may provide a cost-effective, easily accessed safety-planning resource that can be translated into clinical and community practice by multiple health disciplines and advocates. The trial will also provide information about how women in abusive relationships safely access safety information and resources through the Internet. Finally, the trial will inform other research teams on the feasibility and acceptability of fully automated recruitment, eligibility screening, consent and retention procedures.
Trial registration
Trial registered on 03 July 2012 on the Australian New Zealand Clinical Trials Registry ACTRN12612000708853.
PMCID: PMC4314812  PMID: 25637195
Partner abuse; Randomized controlled trial; Protocol; EHealth; Computer-assisted decision making; Internet; Safety; Mental health; Violence; Female
5.  Aripiprazole added to Overweight and Obese Olanzapine-treated Schizophrenia Patients 
Olanzapine treatment has been associated with clinically meaningful weight increases, hypertriglyceridemia, insulin resistance and diabetes mellitus. There are few options for olanzapine-responders who fail other antipsychotic agents. Aripiprazole is a potent (high-affinity) partial agonist at D2 and 5-HT1A receptors and a potent antagonist at 5-HT2A receptor and is associated with less weight gain than olanzapine. We report the results of a 10-week placebo controlled, double-blind crossover study that examined 15 mg/day aripiprazole's effects upon weight, lipids, glucose metabolism, and psychopathology in overweight and obese schizophrenia and schizoaffective disorder subjects treated with a stable dose of olanzapine. During the 4 weeks of aripiprazole treatment there were significant decreases in weight (p = .003) and BMI (p = .004) compared to placebo. Total serum cholesterol (p = .208), HDL-cholesterol (p = .99), HDL-2 (p=.08), HDL-3 (p=.495) and LDL- cholesterol (p=.665) did not change significantly comparing aripiprazole treatment to placebo treatment. However, total serum triglycerides (p = .001), total VLDL-cholesterol (p=.01), VLDL 1- &2-cholesterol (p=.012) decreased significantly during the aripiprazole treatment phase. VLDL-3-cholesterol tended lower during aripiprazole, but the decrease was not significant (p=.062). There was a decrease in c-reactive protein comparing aripiprazole treatment to placebo though it did not reach significance (p=.087). The addition of aripiprazole to a stable dose of olanzapine was well tolerated and resulted in significant improvements on several outcome measures that predict risk for medical morbidity.
PMCID: PMC4311767  PMID: 19512978
Aripiprazole; Olanzapine; Schizophrenia; Lipid Metabolism; Medical Morbidity
6.  Impact of brain tissue filtering on neurostimulation fields: a modeling study 
NeuroImage  2013;85(0 3):1048-1057.
Electrical neurostimulation techniques, such as deep brain stimulation (DBS) and transcranial magnetic stimulation (TMS), are increasingly used in the neurosciences, e.g., for studying brain function, and for neurotherapeutics, e.g., for treating depression, epilepsy, and Parkinson’s disease. The characterization of electrical properties of brain tissue has guided our fundamental understanding and application of these methods, from electrophysiologic theory to clinical dosing-metrics. Nonetheless, prior computational models have primarily relied on ex-vivo impedance measurements. We recorded the in-vivo impedances of brain tissues during neurosurgical procedures and used these results to construct MRI guided computational models of TMS and DBS neurostimulatory fields and conductance-based models of neurons exposed to stimulation. We demonstrated that tissues carry neurostimulation currents through frequency dependent resistive and capacitive properties not typically accounted for by past neurostimulation modeling work. We show that these fundamental brain tissue properties can have significant effects on the neurostimulatory-fields (capacitive and resistive current composition and spatial/temporal dynamics) and neural responses (stimulation threshold, ionic currents, and membrane dynamics). These findings highlight the importance of tissue impedance properties on neurostimulation and impact our understanding of the biological mechanisms and technological potential of neurostimulatory methods.
PMCID: PMC4063680  PMID: 23850466
Neuromodulation; Neurostimulation; TMS; DBS; Cellular models
7.  In vivo performance of a drug-eluting contact lens to treat glaucoma for a month 
Biomaterials  2013;35(1):10.1016/j.biomaterials.2013.09.032.
For nearly half a century, contact lenses have been proposed as a means of ocular drug delivery, but achieving controlled drug release has been a significant challenge. We have developed a drug-eluting contact lens designed for prolonged delivery of latanoprost for the treatment of glaucoma, the leading cause of irreversible blindness worldwide. Latanoprost-eluting contact lenses were created by encapsulating latanoprost–poly(lactic-co-glycolic acid) films in methafilcon by ultraviolet light polymerization. In vitro and in vivo studies showed an early burst of drug release followed by sustained release for one month. Contact lenses containing thicker drug–polymer films demonstrated released a greater amount of drug after the initial burst. In vivo, single contact lenses were able to achieve, for at least one month, latanoprost concentrations in the aqueous humor that were comparable to those achieved with topical latanoprost solution, the current first-line treatment for glaucoma. The lenses appeared safe in cell culture and animal studies. This contact lens design can potentially be used as a treatment for glaucoma and as a platform for other ocular drug delivery applications.
PMCID: PMC3874329  PMID: 24094935
Drug delivery; Contact lens; Sustained release; Latanoprost; Glaucoma; Ocular release
8.  Differential regulation of parvalbumin and calretinin interneurons in the prefrontal cortex during adolescence 
Brain structure & function  2013;219(1):10.1007/s00429-013-0508-8.
Determining the normal developmental trajectory of individual GABAergic components in the prefrontal cortex (PFC) during the adolescent transition period is critical because local GABAergic interneurons are thought to play an important role in the functional maturation of cognitive control that occurs in this developmental window. Based on the expression of calcium-binding proteins, 3 distinctive subtypes of interneurons have been identified in the PFC: parvalbumin (PV)-, calretinin (CR)-, and calbindin (CB)-positive cells. Using biochemical and histochemical measures, we found that the protein level of PV is lowest in juveniles (postnatal day -PD- 25–35) and increases during adolescence (PD45–55) to levels similar to those observed in adulthood (PD65–75). In contrast, the protein expression of CR is reduced in adults compared to juvenile and adolescent animals, whereas CB levels remain mostly unchanged across the developmental window studied here. Semi-quantitative immunostaining analyses revealed that the periadolescent upregulation of PV and the loss of the CR signal appear to be attributable to changes in PV- and CR-positive innervation, which are dissociable from the trajectory of PV- and CR-positive cell number. At the synaptic level, our electrophysiological data revealed that a developmental facilitation of spontaneous glutamatergic synaptic inputs onto PV-positive/fast-spiking interneurons parallels the increase in prefrontal PV signal during the periadolescent transition. In contrast, no age-dependent changes in glutamatergic transmission were observed in PV-negative/non fast-spiking interneurons. Together, these findings emphasize that GABAergic inhibitory interneurons in the PFC undergo a dynamic, cell-type specific remodeling during adolescence and provide a developmental framework for understanding alterations in GABAergic circuits that occur in psychiatric disorders.
PMCID: PMC3665762  PMID: 23400698
interneurons; calcium-binding proteins; prefrontal cortex; fast-spiking; non-fast spiking
9.  T cell recognition of naturally presented epitopes of self-heat shock protein 70 
Cell Stress & Chaperones  2014;19(4):569-578.
Self-reactive T cells have shown to have a potential role as regulators of the immune system preventing or even suppressing autoimmunity. One of the most abundant proteins that can be eluted from human HLA molecules is heat shock protein 70 (HSP70). The aims of the current study are to identify HSP70 epitopes based on published HLA elution studies and to investigate whether T cells from healthy individuals may respond to such self-epitopes. A literature search and subsequent in silico binding prediction based on theoretical MHC binding motifs resulted in the identification of seven HSP70 epitopes. PBMCs of healthy controls proliferated after incubation with two of the seven peptides (H167 and H290). Furthermore H161, H290, and H443 induced CD69 expression or production of cytokines IFNγ or TNFα in healthy controls. The identification of these naturally presented epitopes and the response they elicit in the normal immune system make them potential candidates to study during inflammatory conditions as well as in autoimmune diseases.
Electronic supplementary material
The online version of this article (doi:10.1007/s12192-013-0484-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4041940  PMID: 24425585
Heat shock protein 70; HSP70; Naturally processed T cell epitopes; Human HSP70 peptides; Autoreactive T cells
10.  Trypanosoma brucei Translation Initiation Factor Homolog EIF4E6 Forms a Tripartite Cytosolic Complex with EIF4G5 and a Capping Enzyme Homolog 
Eukaryotic Cell  2014;13(7):896-908.
Trypanosomes lack the transcriptional control characteristic of the majority of eukaryotes that is mediated by gene-specific promoters in a one-gene–one-promoter arrangement. Rather, their genomes are transcribed in large polycistrons with no obvious functional linkage. Posttranscriptional regulation of gene expression must thus play a larger role in these organisms. The eIF4E homolog TbEIF4E6 binds mRNA cap analogs in vitro and is part of a complex in vivo that may fulfill such a role. Knockdown of TbEIF4E6 tagged with protein A-tobacco etch virus protease cleavage site-protein C to approximately 15% of the normal expression level resulted in viable cells that displayed a set of phenotypes linked to detachment of the flagellum from the length of the cell body, if not outright flagellum loss. While these cells appeared and behaved as normal under stationary liquid culture conditions, standard centrifugation resulted in a marked increase in flagellar detachment. Furthermore, the ability of TbEIF4E6-depleted cells to engage in social motility was reduced. The TbEIF4E6 protein forms a cytosolic complex containing a triad of proteins, including the eIF4G homolog TbEIF4G5 and a hypothetical protein of 70.3 kDa, referred to as TbG5-IP. The TbG5-IP analysis revealed two domains with predicted secondary structures conserved in mRNA capping enzymes: nucleoside triphosphate hydrolase and guanylyltransferase. These complex members have the potential for RNA interaction, either via the 5′ cap structure for TbEIF4E6 and TbG5-IP or through RNA-binding domains in TbEIF4G5. The associated proteins provide a signpost for future studies to determine how this complex affects capped RNA molecules.
PMCID: PMC4135740  PMID: 24839125
11.  Cystic Fibrosis and Beckwith-Wiedemann Syndrome: A Case Report 
Cystic fibrosis (CF) is a hereditary disease of exocrine gland function that involves multiple systems but chiefly results in chronic respiratory infections, the major cause of death, pancreatic enzyme deficiency and severe malnutrition, mostly in untreated patients. The association between CF and other inherited diseases or congenital anomalies is rare. We describe for the first time the association of CF and Beckwith-Wiedemann syndrome (BWS). BWS is a genetic disorder commonly characterized by overgrowth. The most common features of BWS include macrosomia, macroglossia, abdominal wall defects, an increased risk for childhood tumors, kidney abnormalities, hypoglycemia in the newborn period and unusual ear creases or pits.
PMCID: PMC4285066  PMID: 25584105
Cystic fibrosis; Beckwith-Wiedemann syndrome; Genetic diseases
12.  The translation initiation complex eIF3 in trypanosomatids and other pathogenic excavates – identification of conserved and divergent features based on orthologue analysis 
BMC Genomics  2014;15(1):1175.
The initiation of translation in eukaryotes is supported by the action of several eukaryotic Initiation Factors (eIFs). The largest of these is eIF3, comprising of up to thirteen polypeptides (eIF3a through eIF3m), involved in multiple stages of the initiation process. eIF3 has been better characterized from model organisms, but is poorly known from more diverged groups, including unicellular lineages represented by known human pathogens. These include the trypanosomatids (Trypanosoma and Leishmania) and other protists belonging to the taxonomic supergroup Excavata (Trichomonas and Giardia sp.).
An in depth bioinformatic search was carried out to recover the full content of eIF3 subunits from the available genomes of L. major, T. brucei, T. vaginalis and G. duodenalis. The protein sequences recovered were then submitted to homology analysis and alignments comparing them with orthologues from representative eukaryotes. Eleven putative eIF3 subunits were found from both trypanosomatids whilst only five and four subunits were identified from T. vaginalis and G. duodenalis, respectively. Only three subunits were found in all eukaryotes investigated, eIF3b, eIF3c and eIF3i. The single subunit found to have a related Archaean homologue was eIF3i, the most conserved of the eIF3 subunits. The sequence alignments revealed several strongly conserved residues/region within various eIF3 subunits of possible functional relevance. Subsequent biochemical characterization of the Leishmania eIF3 complex validated the bioinformatic search and yielded a twelfth eIF3 subunit in trypanosomatids, eIF3f (the single unidentified subunit in trypanosomatids was then eIF3m). The biochemical data indicates a lack of association of the eIF3j subunit to the complex whilst highlighting the strong interaction between eIF3 and eIF1.
The presence of most eIF3 subunits in trypanosomatids is consistent with an early evolution of a fully functional complex. Simplified versions in other excavates might indicate a primordial complex or secondary loss of selected subunits, as seen for some fungal lineages. The conservation in eIF3i sequence might indicate critical functions within eIF3 which have been overlooked. The identification of eIF3 subunits from distantly related eukaryotes provides then a basis for the study of conserved/divergent aspects of eIF3 function, leading to a better understanding of eukaryotic translation initiation.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-1175) contains supplementary material, which is available to authorized users.
PMCID: PMC4320536  PMID: 25539953
Translation initiation factor; Protein synthesis; eIF3; Protozoa
14.  Histoplasmosis After Solid Organ Transplant 
This multicenter retrospective review describes 152 cases of histoplasmosis and provides an epidemiologic analysis of timing, patterns of presentation, treatment, and outcome. Although late cases occur, the first year after solid organ transplant is the period of highest risk for histoplasmosis.
Background. To improve our understanding of risk factors, management, diagnosis, and outcomes associated with histoplasmosis after solid organ transplant (SOT), we report a large series of histoplasmosis occurring after SOT.
Methods. All cases of histoplasmosis in SOT recipients diagnosed between 1 January 2003 and 31 December 2010 at 24 institutions were identified. Demographic, clinical, and laboratory data were collected.
Results. One hundred fifty-two cases were identified: kidney (51%), liver (16%), kidney/pancreas (14%), heart (9%), lung (5%), pancreas (2%), and other (2%). The median time from transplant to diagnosis was 27 months, but 34% were diagnosed in the first year after transplant. Twenty-eight percent of patients had severe disease (requiring intensive care unit admission); 81% had disseminated disease. Urine Histoplasma antigen detection was the most sensitive diagnostic method, positive in 132 of 142 patients (93%). An amphotericin formulation was administered initially to 73% of patients for a median duration of 2 weeks; step-down therapy with an azole was continued for a median duration of 12 months. Ten percent of patients died due to histoplasmosis with 72% of deaths occurring in the first month after diagnosis; older age and severe disease were risk factors for death from histoplasmosis. Relapse occurred in 6% of patients.
Conclusions. Although late cases occur, the first year after SOT is the period of highest risk for histoplasmosis. In patients who survive the first month after diagnosis, treatment with an amphotericin formulation followed by an azole for 12 months is usually successful, with only rare relapse.
PMCID: PMC3814825  PMID: 24046304
histoplasmosis; fungal infection; solid organ transplant
15.  Exploring the Utility of Ultra-Brief Delirium Assessments in a Nonintensive Care Geriatric Population: The GEM Study 
The Gerontologist  2012;53(6):1051-1055.
Objective: To determine how an ultra-brief structured tool that would require usually less than a minute for delirium assessment compares with a clinical assessment based on Diagnostic and Statistical Manual-IV (DSM-IV) in a geriatric postacute care (PAC) rehabilitation unit. Design: Prospective observational cohort study. Setting: Postacute geriatric hospital ward of a Veteran’s Affairs hospital. Participants: Consecutively admitted patients between 50 and 100 years old for inpatient postacute medical care. Measurements: Two teams, blinded to one another’s evaluations, performed daily delirium assessments using either the Confusion Assessment Method for the intensive care unit (CAM-ICU) or clinical assessment based on DSM-IV. Results: There were 61 patients enrolled (median 73 years old, range: 52–94), who underwent 521 paired observations. Delirium was detected in 18 patients (29.5%) by one of the two screening methods over the course of the study, most of whom (14 patients, 23%) were delirious on the first day of enrollment. Delirium was identified by the CAM-ICU on 12.6% of the observations and by the clinical assessment on 6% of the observations (κ = 0.25, 95% confidence interval [CI]: 0.09, 0.40). Examination of disagreement between the 2 evaluations revealed that patients with dementia (κ = 0.11, 95% CI: −0.14, 0.27) had 10.7 times higher odds (95% CI: [3.1, 36.8], p value < .001) of having discordance than patients without dementia. Conclusions: Different delirium assessments may disagree depending on the study population. Dementia patients are especially challenging to evaluate for delirium.
PMCID: PMC3826161  PMID: 23231946
Dementia; Clinical practice; Delirium.
16.  Why Words are Hard for Adults with Developmental Language Impairments 
To determine whether word learning problems associated with developmental language impairment (LI) reflect deficits in encoding or subsequent remembering of forms and meanings.
Sixty-nine 18-25-year-olds with LI or without (ND) took tests to measure learning of 16 word forms and meanings immediately after training (encoding) and 12-hours, 24-hours, and 1-week later (remembering). Half of the participants trained in the morning and half in the evening.
At immediate posttest, those with LI performed more poorly on form and meaning than those with ND. Poor performance was more likely among those with more severe LI. The LI and ND groups demonstrated no difference in remembering word meanings over one week. In both groups, participants who trained in the evening, and therefore slept shortly after training, demonstrated greater gains in meaning recall than those who trained in the morning. In contrast, the LI-ND gap for word form recall widened over the week.
Some adults with LI have encoding deficits that limit the addition of word forms and meanings to the lexicon. Similarities and differences in patterns of remembering in the LI and ND groups motivate the hypothesis that consolidation of declarative memory is a strength for adults with LI.
PMCID: PMC3951710  PMID: 24023376
17.  Nonnucleoside Inhibitors of Norovirus RNA Polymerase: Scaffolds for Rational Drug Design 
Norovirus (NoV) is the leading cause of acute gastroenteritis worldwide, causing over 200,000 deaths a year. NoV is nonenveloped, with a single-stranded RNA genome, and is primarily transmitted person to person. The viral RNA-dependent RNA polymerase (RdRp) is critical for the production of genomic and subgenomic RNA and is therefore a prime target for antiviral therapies. Using high-throughput screening, nearly 20,000 “lead-like” compounds were tested for inhibitory activity against the NoV genogroup II, genotype 4 (GII.4) RdRp. The four most potent hits demonstrated half-maximal inhibitory concentrations (IC50s) between 5.0 μM and 9.8 μM against the target RdRp. Compounds NIC02 and NIC04 revealed a mixed mode of inhibition, while NIC10 and NIC12 were uncompetitive RdRp inhibitors. When examined using enzymes from related viruses, NIC02 demonstrated broad inhibitory activity while NIC04 was the most specific GII.4 RdRp inhibitor. The antiviral activity was examined using available NoV cell culture models; the GI.1 replicon and the infectious GV.1 murine norovirus (MNV). NIC02 and NIC04 inhibited the replication of the GI.1 replicon, with 50% effective concentrations (EC50s) of 30.1 μM and 71.1 μM, respectively, while NIC10 and NIC12 had no observable effect on the NoV GI.1 replicon. In the MNV model, NIC02 reduced plaque numbers, size, and viral RNA levels in a dose-dependent manner (EC50s between 2.3 μM and 4.8 μM). The remaining three compounds also reduced MNV replication, although with higher EC50s, ranging from 32 μM to 38 μM. In summary, we have identified novel nonnucleoside inhibitor scaffolds that will provide a starting framework for the development and future optimization of targeted antivirals against NoV.
PMCID: PMC4068436  PMID: 24637690
18.  Attitudes of nurses and physicians towards nurse-physician collaboration in northwest Ethiopia: a hospital based cross-sectional study 
BMC Nursing  2014;13(1):37.
Collaboration between professionals is important in health institutions where most activities are team-performed. Ineffective nurse-physician collaboration affects patient outcome, nurses’ job satisfaction and organizational cost and is challenged by personal, interpersonal and organizational factors. The main objective of this study was to assess attitudes of nurses and physicians towards nurse-physician collaboration and the level of satisfaction with regard to quality of collaboration between them at Referral Hospitals of Northwest Ethiopia, from February 1st to April 30, 2013.
An institution based cross-sectional study was conducted among 176 nurses and 53 physicians working in Felegehiwot and Gondar University Referral Hospitals. Data were collected using self-administered questionnaires. Attitudes of nurses and physicians were measured using Jefferson scale of attitudes towards nurse-physician Collaboration. Results were summarized using descriptive statistics and difference of means and proportions were evaluated using student t test p <0.05 was considered as significant.
The overall response rate was 90.50%. Nurses demonstrate more favorable attitudes than physicians with mean score of 49.63 and 47.49 and standard error of mean 0.474 and 0.931 respectively with p = 0.043. For the Jefferson Scale Attitudes towards Nurse-Physician Collaboration includes four subscales, which are: 1) shared education and teamwork, 2) Caring vs curing, 3) nurses autonomy and 4) physician dominance. Nurses scored higher on three subscales (1, 2 and 4). However, statistically significant differences were noted with regard to subscales 2 and 4 (p = 0.01, p = 0.004, respectively).
This study identified that neither nurses nor physicians were satisfied with their current collaboration and nurses demonstrated less satisfaction with the current nurse physician collaboration. As compared with physicians nurses had more favorable attitudes towards collaboration specifically toward nurses’ contributions to the psychosocial and educational aspects of patient care, and stronger rejection of a totally dominant physician role.
PMCID: PMC4245739  PMID: 25431536
Attitudes; Collaboration; Nurse; Physician; Nurse-physician
19.  Of ‘Disgrace’ and ‘Pain’ – Corticolimbic Interaction Patterns for Disorder-Relevant and Emotional Words in Social Phobia 
PLoS ONE  2014;9(11):e109949.
Limbic hyperactivation and an impaired functional interplay between the amygdala and the prefrontal cortex are discussed to go along with, or even cause, pathological anxiety. Within the multi-faceted group of anxiety disorders, the highly prevalent social phobia (SP) is characterized by excessive fear of being negatively evaluated. Although there is widespread evidence for amygdala hypersensitivity to emotional faces in SP, verbal material has rarely been used in imaging studies, in particular with an eye on disorder-specificity. Using functional magnetic resonance imaging (fMRI) and a block design consisting of (1) overall negative, (2) social-phobia related, (3) positive, and (4) neutral words, we studied 25 female patients with social phobia and 25 healthy female control subjects (HC). Results demonstrated amygdala hyperactivation to disorder-relevant but not to generally negative words in SP patients, with a positive correlation to symptom severity. A functional connectivity analysis revealed a weaker coupling between the amygdala and the left middle frontal gyrus in patients. Symptom severity was negatively related to connectivity strength between the amygdala and the ventromedial prefrontal and orbitofrontal cortex (Brodmann Area 10 and 11). The findings clearly support the view of a hypersensitive threat-detection system, combined with disorder-related alterations in amygdala-prefrontal cortex connectivity in pathological anxiety.
PMCID: PMC4232246  PMID: 25396729
20.  “You Are Such a Disappointment!”: Negative Emotions and Parents’ Perceptions of Adult Children’s Lack of Success 
Parents’ perceptions of their adult children’s successes (or lack thereof) may be associated in different ways with discrete negative emotions (e.g., guilt, anger, disappointment, and worry). Furthermore, mothers and fathers may vary in their reactions to children’s success in different domains.
Participants included 158 mothers and fathers from the same families (N = 316) and their adult child. Mothers and fathers evaluated their adult children’s successes in (a) career and (b) relationship domains. Mothers and fathers also reported on several negative emotions in the parent–child tie: guilt, anger, disappointment, and worry.
For fathers, perceptions of children’s poorer career success were associated with disappointment, anger, and guilt. Mothers’ perceptions of children’s lack of career success were associated with disappointment and worry. Mothers’ perceptions of children’s poorer success in relationships were associated with each of the negative emotions, with the exception of anger.
Parents experience emotions associated with unmet goals and future concerns in relationships with less successful children. Mothers may respond emotionally to career and relationship success, whereas fathers may respond emotionally primarily to their child’s career success. Findings underscore the importance of considering the context of parents’ negative emotional experiences in ties to adult children.
PMCID: PMC3805291  PMID: 23733857
Achievements; Negative emotions; Parent–adult child relationships; Success.
21.  CB1 cannabinoid receptor stimulation during adolescence impairs the maturation of GABA function in the adult rat prefrontal cortex 
Molecular psychiatry  2014;19(5):536-543.
Converging epidemiological studies indicate that cannabis abuse during adolescence increases the risk of developing psychosis and prefrontal cortex (PFC)-dependent cognitive impairments later in life. However, the mechanisms underlying the adolescent susceptibility to chronic cannabis exposure are poorly understood. Given that the psychoactive constituent of cannabis binds to the CB1 cannabinoid receptor, the present study was designed to determine the impact of a CB1 receptor agonist (WIN) during specific windows of adolescence on the functional maturation of the rat PFC. By means of local field potential (LFP) recordings and ventral hippocampal stimulation in vivo, we found that a history of WIN exposure during early (postnatal day -P- 35-40) or mid-(P40-45) adolescence, but not in late adolescence (P50-55) or adulthood (P75-80), is sufficient to yield a state of frequency-dependent prefrontal disinhibition in adulthood comparable to that seen in the juvenile PFC. Remarkably, this prefrontal disinhibition could be normalized following a single acute local infusion of the GABA-Aα1 positive allosteric modulator Indiplon, suggesting that adolescent exposure to WIN causes a functional downregulation of GABAergic transmission in the PFC. Accordingly, in vitro recordings from adult rats exposed to WIN during adolescence demonstrate that local prefrontal GABAergic transmission onto layer V pyramidal neurons is markedly reduced to the level seen in the P30-35 PFC. Together, these results indicate that early and mid-adolescence constitute a critical period during which repeated CB1 receptor stimulation is sufficient to elicit an enduring state of PFC network disinhibition resulting from a developmental impairment of local prefrontal GABAergic transmission.
PMCID: PMC3999247  PMID: 24589887
prefrontal cortex; CB1 receptor; adolescence; GABA; cannabinoid; ventral hippocampus
22.  Assessment of cross-frequency coupling with confidence using generalized linear models 
Journal of neuroscience methods  2013;220(1):10.1016/j.jneumeth.2013.08.006.
Brain voltage activity displays distinct neuronal rhythms spanning a wide frequency range. How rhythms of different frequency interact – and the function of these interactions – remains an active area of research. Many methods have been proposed to assess the interactions between different frequency rhythms, in particular measures that characterize the relationship between the phase of a low frequency rhythm and the amplitude envelope of a high frequency rhythm. However, an optimal analysis method to assess this cross-frequency coupling (CFC) does not yet exist.
New Method
Here we describe a new procedure to assess CFC that utilizes the generalized linear modeling (GLM) framework.
We illustrate the utility of this procedure in three synthetic examples. The proposed GLM-CFC procedure allows a rapid and principled assessment of CFC with confidence bounds, scales with the intensity of the CFC, and accurately detects biphasic coupling.
Comparison with Existing Methods
Compared to existing methods, the proposed GLM-CFC procedure is easily interpretable, possesses confidence intervals that are easy and efficient to compute, and accurately detects biphasic coupling.
The GLM-CFC statistic provides a method for accurate and statistically rigorous assessment of CFC.
PMCID: PMC3813466  PMID: 24012829
Phase-amplitude coupling; oscillations; theta; gamma
23.  18F-Alfatide II and 18F-FDG Dual Tracer Dynamic PET for Parametric, Early Prediction of Tumor Response to Therapy 
A single dynamic PET acquisition using multiple tracers administered closely in time could provide valuable complementary information about a tumor’s status under quasi-constant conditions. This study aims to investigate the utility of dual-tracer dynamic PET imaging with 18F-Alfatide II (18F-AlF-NOTA-E[PEG4-c(RGDfk)]2) and 18F-FDG for parametric monitoring of tumor responses to therapy.
We administered doxorubicin to one group of athymic nude mice with U87MG tumors and Abraxane to another group of mice with MDA-MB-435 tumors. To monitor therapeutic responses, we performed dual-tracer dynamic imaging, in sessions that lasted 90 min, starting by injecting the mice via tail vein catheters with 18F-Alfatide II, followed 40 minutes later by 18F-FDG. To achieve signal separation of the two tracers, we fit a three-compartment reversible model to the time activity curve (TAC) of 18F-Alfatide II for the 40 min prior to 18F-FDG injection, and then extrapolated to 90 min. The 18F-FDG tumor TAC was isolated from the 90 min dual tracer tumor TAC by subtracting the fitted 18F-Alfatide II tumor TAC. With separated tumor TACs, the 18F-Alfatide II binding potential (Bp=k3/k4) and volume of distribution (VD), and 18F-FDG influx rate ((K1×k3)/(k2 + k3)) based on the Patlak method were calculated to validate the signal recovery in a comparison with 60-min single tracer imaging and to monitor therapeutic response.
The transport and binding rate parameters K1-k3 of 18F-Alfatide II, calculated from the first 40 min of dual tracer dynamic scan, as well as Bp and VD, correlated well with the parameters from the 60 min single tracer scan (R2 > 0.95). Compared with the results of single tracer PET imaging, FDG tumor uptake and influx were recovered well from dual tracer imaging. Upon doxorubicin treatment, while no significant changes in static tracer uptake values of 18F-Alfatide II or 18F-FDG were observed, both 18F-Alfatide II Bp and 18F-FDG influx from kinetic analysis in tumors showed significant decreases. For Abraxane therapy of MDA-MB-435 tumors, significant decrease was only observed with 18F-Alfatide II Bp value from kinetic analysis but not 18F-FDG influx.
The parameters fitted with compartmental modeling from the dual tracer dynamic imaging are consistent with those from single tracer imaging, substantiating the feasibility of this methodology. Even though no significant differences in tumor size were found until 5 days after doxorubicin treatment started, at day 3 there were already substantial differences in 18F-Alfatide II Bp and 18F-FDG influx rate. Dual tracer imaging can measure 18F-Alfatide II Bp value and 18F-FDG influx simultaneously to evaluate tumor angiogenesis and metabolism. Such changes are known to precede anatomical changes, and thus parametric imaging may offer the promise of early prediction of therapy response.
PMCID: PMC4209961  PMID: 24232871
dual-tracer dynamic PET; parametric imaging; 18F-Alfatide II; 18F-FDG; therapy response
24.  Direct mobilisation of lysosomal Ca2+ triggers complex Ca2+ signals 
Journal of cell science  2012;126(0 1):60-66.
Accumulating evidence implicates acidic organelles of the endolysosomal system as mobilisable stores of Ca2+ but their relationship to the better-characterised endoplasmic reticulum (ER) Ca2+ store remains unclear. Here we show that rapid osmotic permeabilisation of lysosomes evokes prolonged, spatiotemporally complex Ca2+ signals in primary cultured human fibroblasts. These Ca2+ signals comprised an initial response that correlated with lysosomal disruption and secondary long-lasting spatially heterogeneous Ca2+ oscillations that required ER-localised inositol trisphosphate receptors. Electron microscopy identified extensive membrane contact sites between lysosomes and the ER. Mobilisation of lysosomal Ca2+ stores is thus sufficient to evoke ER-dependent Ca2+ release probably through lysosome-ER membrane contact sites, and akin to the proposed mechanism of action of the Ca2+ mobilising messenger nicotinic acid adenine dinucleotide phosphate (NAADP). Our data identify functional and physical association of discrete Ca2+ stores important for the genesis of Ca2+ signal complexity.
PMCID: PMC4208295  PMID: 23108667
Ca2+; Lysosomes; Endoplasmic reticulum; Membrane contact sites; NAADP
25.  Neuroanatomical Profiles of Deafness in the Context of Native Language Experience 
The Journal of Neuroscience  2014;34(16):5613-5620.
The study of congenitally deaf adult humans provides an opportunity to examine neuroanatomical plasticity resulting from altered sensory experience. However, attributing the source of the brain's structural variance in the deaf is complicated by the fact that deaf individuals also differ in their language experiences (e.g., sign vs spoken), which likely influence brain anatomy independently. Although the majority of deaf individuals in the United States are born to hearing parents and are exposed to English, not American Sign Language (ASL) as their first language, most studies on deafness have been conducted with deaf native users of ASL (deaf signers). This raises the question of whether observations made in deaf signers can be generalized. Using a factorial design, we compared gray (GMV) and white (WMV) matter volume in deaf and hearing native users of ASL, as well as deaf and hearing native users of English. Main effects analysis of sensory experience revealed less GMV in the deaf groups combined (compared with hearing groups combined) in early visual areas and less WMV in a left early auditory region. The interaction of sensory experience and language experience revealed that deaf native users of English had fewer areas of anatomical differences than did deaf native users of ASL (each compared with their hearing counterparts). For deaf users of ASL specifically, WMV differences resided in language areas such as the left superior temporal and inferior frontal regions. Our results demonstrate that cortical plasticity resulting from deafness depends on language experience and that findings from native signers cannot be generalized.
PMCID: PMC3988414  PMID: 24741051
deafness; language; native users of American Sign Language; native users of English; VBM

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